Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.8 (cholinesterase)
12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HI-6 and TMB-4 were the most effective and safe of 7 cholinesterase reactivators tested as agents for the prophylaxis of proserine poisoning of male mice. The reactivator HI-6 strongly potentiated the prophylactic efficacy of a mixture of atropine and arpenal administered in the doses sufficient for the blockade of both the m- and h-cholinoreactive systems of mice. As demonstrated by experiments in vitro, HI-6 and TMB-4 did not reacivate proserine-inhibited cholinesterase. The natural anticholinesterase activity of HI-6 was negligible. Based on the correlation of the data obtained to the reported data indicating that HI-6 has a low ganglioblocking activity it is inferred that the direct effect on the receptor is of no importance for the potentiating effect. It is assumed that HI-6 modulates the cholinoreactive systems, which leads to a dramatic increase of the efficacy of cholinolytics.
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PMID:[Trial of cholinesterase reactivators as proserine antagonists]. 635

It has been shown in rat experiments that armin in doses that inhibit blood cholinesterase by 50 and more per cent lowers the content of nicotinamide coenzymes in the myocardium and liver of the animals, primarily at the expense of the diminution of the oxidized forms. In the rat liver, armin decreases the content of adenyl nucleotides, mainly at the expense of ATP. Dipyroxime prevents changes induced by armin, which is accompanied by partial reactivation of cholinesterase. It is suggested that in the mechanism of antidote action of dipyroxime, of importance is its normalizing effect on redox and energy processes in the body.
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PMID:[Effect of armin and dipyroxime on the nicotinamide coenzyme and adenine nucleotide content of the rat myocardium and liver]. 705 78

The authors found that the phosphororganic pesticide neguvon in a dose of 200 mg/kg of body weight diminished the content of dopamine in the striatum of white rats. This effect was increased after daily administration of the same dose for a period of 5 days. The reactivator of cholinesterase TMB-4 and H-choline blocker tropacine prevented this effect. They discussed the connection between the changes in the content of dopamine and modulating role of presynaptic choline receptors of H- and M- types in the dopaminergic terminals of the striatum.
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PMID:[Effect of the organophosphorus compound neguvon on the dopamine content in the rat brain]. 725 22

Membrane-bound bovine erythrocyte acetylcholinesterase was inhibited with physostigmine or carbaryl, and the rate constants of carbamylation and decarbamylation were determined from the proportion of inhibited acetylcholinesterase in the steady state, and the rate of approach to the steady state. The oximes 2-PAM, HI-6, HS-6, TMB-4 and toxogonin, at 0.1 mM, all decreased the rate of carbamylation by physostigmine, but increased the rate of carbamylation by carbaryl. TMB-4 and toxogonin were the most effective oximes in potentiating carbamylation by carbaryl, with an enhancement of the second-order rate constant of 54- and 17-fold respectively. The greatest reduction in the rate constant for carbamylation by physostigmine (3.7-fold) was caused by HI-6. HS-6 and HI-6 increased the rate of decarbamylation, while 2-PAM reduced the rate of decarbamylation if physostigmine was the carbamate. 2-PAM and HI-6 were also studied with soluble bovine erythrocyte acetylcholinesterase, and similar results were obtained. The results extend those in a recent report by other authors who studied the half-life of carbamylation for acetylcholinesterase and butyrylcholinesterase in an attempt to understand the mechanism by which oximes increase the toxicity of carbaryl in vivo. These authors proposed binding of the oximes to an allosteric site on the enzyme. While not discounting this possibility, the present results, taken with other reports in the literature, suggest that binding of the oximes to the anionic subsite of the active site of the enzyme is also feasible. The present results also offer an explanation for another recent report, in which anomalous results were presented for decarbamylation of physostigmine-inhibited and carbaryl-inhibited erythrocyte acetylcholinesterase in the presence of 2-PAM or HI-6.
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PMID:Rate constants of carbamylation and decarbamylation of acetylcholinesterase for physostigmine and carbaryl in the presence of an oxime. 816 44

The properties of aminostigmine in comparison with those of other carbamate inhibitors of cholinesterases have been studied in vitro using potentiometric titration and Ellman methods. The bimolecular constants of the inhibition rate of acetyl-, butyryl- and propionylcholinesterase were found to be equal to (8.0-14.0).10(5) (3.8-7.7).10(5) and 11.0.10(5) M-1.min-1, respectively. In terms of inhibitory activity, aminostrigmine is comparable to neostigmine methylsulphate, being inferior to physostigmine and superior to pyridistigmine. The rate of decarbamylation of acetylcholinesterase inhibited by aminostigmine measured by the dilution method, by creating excessive acetylcholine and by dialysis is characterized by k2c constants equal to (1.1-1.6).10(-2), (2.5-2.8).10(-2) and 0.025.10(-2) min-1, respectively. On the whole, aminostigmine belongs to slowly reversible inhibitors. Being carbamylated by aminostigmine, the enzyme is resistant to reactivation by TMB-4 and HI-6. At (4-6).10(-7) M aminostigmine prevents by 50% the irreversible binding of cholinesterase by certain organophosphate inhibitors of cholinesterase when the latter are used at concentrations needed to inhibit the enzymatic activity by 85-90%.
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PMID:[Biochemical characteristics of aminostigmine--a new anticholinesterase agent]. 872 87

The potential of obidoxime and other pyridinium-4-aldoximes to reactivate dimethyl- and diethylphosphorylated cholinesterases is markedly restricted by the inevitable formation of rather stable phosphoryl oximes (POXs) with high anticholinesterase activity. This effect is hardly seen with very dilute enzyme preparations, but becomes significant at physiological enzyme concentrations. Human plasma with the butyrylcholinesterase irreversibly blocked by soman was able to stimulate obidoxime-induced reactivation of concentrated erythrocyte acetylcholinesterase (Ery-AChE) to the same extent as was observed with a dilute preparation, suggesting phosphoryl oxime-destroying capacity. The inactivating factor, which was tentatively termed POX-hydrolase, had (1) a molecular weight of >100 kDa; (2) required Ca2+ , which could not be substituted by Zn2+ or Mg2+; and (3) lost its catalytic activity reversibly in the presence of ethylenediamine-tetraacetic acid (EDTA). The enzyme activity varied widely (20-fold) among different subjects and did not follow the activity pattern of human serum paraoxonase (PON1). Rabbit plasma with its particularly high paraoxonase content showed only weak POX-hydrolase activity. These data suggest POX-hydrolase to be a different entity. POX-hydrolase was most active with the putative phosphoryl-obidoxime from paraoxon-ethyl, less with the product from paraoxon-methyl and least with that from diisopropylfluorophosphate. The analogue TMB-4 reacted similarly to obidoxime. The putative phosphonyl oximes arising by the reaction of obidoxime with nerve agents were apparently not cleaved. The variation in POX-hydrolase activity may additionally contribute to the variable response to oxime therapy in patients with organophosphate insecticide poisoning.
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PMID:The phosphoryl oxime-destroying activity of human plasma. 1081 64

Seizures and status epilepticus, which may contribute to brain injury, are common consequences of exposure to organophosphorus (OP) cholinesterase inhibitors. Effective management of these seizures is critical. To investigate the efficacy of nasal midazolam as an anticonvulsive treatment for OP exposure, as compared to intramuscular midazolam, guinea pigs were connected to a recording swivel for electrocorticograph (ECoG) monitoring and clinical observation. The experimental paradigm consisted of pyridostigmine pretreatment (0.1 mg/kg i.m.) 20 min prior to sarin exposure (1.2x LD(50,) 56 micro g/kg i.m.). One minute post-exposure, atropine (3 mg/kg i.m.) and TMB-4 (1 mg/kg im) were administered. Within 3-8 min after sarin exposure all animals developed electrographic seizure activity (EGSA), with convulsive behavior. Treatment with midazolam (1 mg/kg i.m.) 10 min after the onset of EGSA abolished EGSA within 389+/-181 s. The same dose was not effective, in most cases, when given 30 min after onset. However, a higher dose (2 mg/kg) was found efficacious after 30 min (949+/-466 s). In contrast, nasal application of midazolam (1 mg/kg) was found most effective, with significant advantages, in amelioration of EGSA and convulsive behavior, when given 10 min (216+/-185 s) or 30 min (308+/-122 s) following the onset of EGSA ( P<0.001). Thus, nasal midazolam could be used as a novel, rapid and convenient route of application against seizure activity induced by nerve agent poisoning.
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PMID:Nasal midazolam as a novel anticonvulsive treatment against organophosphate-induced seizure activity in the guinea pig. 1263 57

Pralidoxime chloride (pyridine-2-aldoxime methochloride; Protopam Chloride) and 1,1'-trimethylenebis(4-hydroxyiminomethylpyridinium bromide) (TMB-4) antagonize the spasm of the isolated or intact small intestine of the rabbit caused by the anticholinesterase, echothiophate iodide (S-2-dimethylaminoethyl OO-diethyl phosphorothiolate methiodide; Phospholine Iodide). In vitro, both oximes also antagonize the spasm caused by acetylcholine. The quantitative relationships have been studied in comparison with the activity of atropine against echothiophate and acetylcholine. Echothiophate-treated intestine which is subjected to a concentration of oxime sufficient to cause 100% restoration of function (but not cholinesterase reactivation) will go back into spasm on washing out both drugs. Strips treated with a high concentration of oxime, sufficient to cause 100% reactivation of cholinesterase, exhibit normal control tone and motility after washing. It is concluded that pralidoxime and 1,1'-trimethylenebis(4-hydroxyiminomethylpyridinium bromide) have an anticholinergic action as well as the ability to reactivate cholinesterase and that this action plays a significant part in the initial recovery of function under the conditions of these experiments.
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PMID:Mechanism of the antagonism by pralidoxime and 1,1-trimethylenebis(4-hydroxyiminomethylpyridinium) of the action of echothiphate on the intestine. 1446 53

A novel series of acetylcholinesterase (AChE) inhibitors of the bispyridinium type was synthesized and the inhibitory activity against AChE and butyrylcholinesterase (BChE) measured. In essence, the substitution pattern influenced the inhibitory potency against AChE, where the most active bispyridiniumoxime (TMB-4) was bisbenzyl substituted followed by monobenzyl substituted, bismethyl substituted, and unsubstituted derivatives of TMB-4. Hence, the bisbenzyl ether of TMB-4 was further investigated. In order to obtain diverse lipophilic and electronic properties for these bisbenzyl bispyridinium derivatives (so-called DUO series), the lateral ring substitution was systematically varied. The lowest IC(50) value against AChE found thus far in the DUO series was 0.34 microM. Docking studies were carried out to elucidate the differences in biological activity. A general binding mode for nearly all compounds could be identified by these investigations. In this binding mode, the docked ligands span the narrow, deeply buried active-site gorge, interacting with Trp84 at the bottom of the gorge, Tyr334 or Phe331 halfway down the gorge, and Trp279 at the peripheral anionic site at the mouth of the gorge. For specific ligands, additional interactions were found which helped to explain their deviating activity. Based on the promising characteristics of the novel acetylcholinesterase inhibitors presented, a series of structurally related, optimized candidates will be developed.
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PMID:Synthesis, biological activity, and docking studies of new acetylcholinesterase inhibitors of the bispyridinium type. 1463 45

The neurochemical effects of repeated postnatal exposure to chlorpyrifos (CPS) were studied in developing rats. Rats were gavaged daily from postnatal day (PND) 1-21 with CPS in corn oil starting at 1.5 mg/kg (low dosage group) and increasing gradually to 3 mg/kg and then to 6 mg/kg (high dosage group). Brain cholinesterase (ChE) activity was significantly inhibited on PND 6, 12, 22, and 30, with maximum inhibition on PND 6 of 49 and 59% and recovering to 18 and 33% on PND 30 in the low and high dosage groups, respectively. On PND 22 and 30, 94% or greater of the inhibited ChE could not be reactivated by the oxime TMB-4 in both treatment groups, indicating aging of the phosphorylated ChE. Total muscarinic acetylcholine receptors (mAChR) were reduced in a dose-related manner on PND 12 and 22, with substantial recovery by PND 30. M1/M3 mAChR were significantly reduced on PND 6 and 12 only in the high dosage group, and on PND 22 in both groups, while M2/M4 mAChR were reduced in the high dosage group on PND 22 and 30. On PND 30 choline acetyltransferase activity and vesicular acetylcholine transporter levels were decreased by 12 and 22%, respectively, only in the high dosage group. High-affinity choline transporter levels were decreased at all time points in the high dosage group and on PND 6, 22, and 30 in the low dosage group. The results presented here demonstrate that repeated postnatal exposures to CPS result in transient reductions of mAChR and more persistent alterations of presynaptic cholinergic neurons. In addition, the long-term reduction of brain ChE activity observed following repeated postnatal exposure to CPS is attributable to permanent inactivation or "aging" of the enzyme.
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PMID:Effects of repeated oral postnatal exposure to chlorpyrifos on cholinergic neurochemistry in developing rats. 1564


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